Reducing Cholesterol in Macrophage Activates NF-kB through Mitochondria, Resulting in Epigenomic Reprogramming to Dampen Inflammation
Reducing Cholesterol in Macrophage Activates NF-kB through Mitochondria, Resulting in Epigenomic Reprogramming to Dampen Inflammation
Cholesterol plays an important role in macrophage functions including their immune response1. Recently, NF-kB was shown to reprogram the epigenome in macrophages2. Here, we show that NF-kB pathway is activated in resting macrophages when cholesterol is reduced by statin or methyl-β-cyclodextrin (MCD). Activated NF-kB increases the expression of histone-modifying enzymes, such as demethylase JMJD3. We provide evidence that the epigenome in these macrophages is reprogrammed, likely driven by NF-kB and histone modifications2. We also show that cholesterol reduction in macrophages results in suppression of mitochondria respiration. Specifically, cholesterol levels in the inner membrane of the mitochondria is reduced, which impairs the efficiency of ATP synthase (complex V). Consequently, protons accumulate in the intermembrane space to active NF-kB and JMJD3, thereby modifying the epigenome. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (LPS), cholesterol-reduced macrophages generate responses that are less pro-inflammatory and more homeostatic, which should favour inflammation resolution. Taken together, we describe a mechanism by which the level of mitochondrial cholesterol in resting macrophages regulates the epigenome through NF-kB, thereby preparing macrophage for future immune activation.
Zha Xiaohui、Salloum Zeina、Dauner Kristin、Verma Neha、Valdivieso-Gonz¨￠lez David、L¨?pez-Montero Iv¨￠n、Nakka Kiran、Almendro-Vedia V¨actor、Sorisky Alexander、Bandukwala Hina、Dilworth Jeffery、McDonald Jeffery
Chronic Disease Program, Ottawa Hospital Research Institute||Department of Medicine and of Biochemistry, Microbiology & Immunology, University of OttawaChronic Disease Program, Ottawa Hospital Research InstituteChronic Disease Program, Ottawa Hospital Research InstituteChronic Disease Program, Ottawa Hospital Research InstituteDepartamento Qu¨amica F¨asica, Universidad Complutense de Madrid||Instituto de Investigaci¨?n Hospital Doce de Octubre (imas12)Departamento Qu¨amica F¨asica, Universidad Complutense de Madrid||Instituto de Investigaci¨?n Hospital Doce de Octubre (imas12)Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research InstituteDepartamento Qu¨amica F¨asica, Universidad Complutense de Madrid||Instituto de Investigaci¨?n Hospital Doce de Octubre (imas12)Chronic Disease Program, Ottawa Hospital Research Institute||Department of Medicine and of Biochemistry, Microbiology & Immunology, University of OttawaSprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research InstituteSprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute||Department of Cellular and Molecular Medicine, University of OttawaDepartment of Molecular Genetics, The University of Texas Southwestern Medical Center
基础医学生物化学分子生物学
Zha Xiaohui,Salloum Zeina,Dauner Kristin,Verma Neha,Valdivieso-Gonz¨￠lez David,L¨?pez-Montero Iv¨￠n,Nakka Kiran,Almendro-Vedia V¨actor,Sorisky Alexander,Bandukwala Hina,Dilworth Jeffery,McDonald Jeffery.Reducing Cholesterol in Macrophage Activates NF-kB through Mitochondria, Resulting in Epigenomic Reprogramming to Dampen Inflammation[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2022.02.10.479926.点此复制
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